Process for preparing flavonoids

ABSTRACT

A simple and easy process for preparing pharmacologically useful flavonoid compound having reductase inhibitory effect, active oxygen extinguishing effect, carcinogenesis promotion inhibitory effect, anti-inflammatory effect, and so on. Particularly, a process for preparing the compound of the formula (I):                    
     wherein, R 2  is a substituted or un-substituted phenyl group; R 7  is a hydrogen atom or a hydroxyl group; and n is an integer of 1 to 4; 
     by bonding a sugar derivative to catechins as the starting compound selectively via O-glycoside bond and then oxidizing the 4-position of flavanoid skeleton of the obtained compound.

This application is a 371 of PCT/JP01/01674 filed Mar. 5, 2001.

TECHNICAL FIELD

The present invention relates to a process for preparing flavonoidcompound useful for treating many kinds of diseases due to their aldosereductase inhibitory effect, active oxygen extinguishing effect,carcinogenesis promotion inhibitory effect, anti-inflammatory effect,and so on. More particularly, the present invention relates to a processfor preparing astilbin, neoastilbin, isoastilbin, neoisoastilbin,cuersetin, smitilbin, engeletin, and analogous thereof.

BACKGROUND ART

Astilbin represented by the following formula (I-c):

is one of dihydroflavonol glycoside isolated from root of Astilbethunbergii Miq., which is herbaceous perennial of saxifragaceous, aswell as from the plant matter of Asmilaxylabra, Engelhardtia,Lyoniaovalifolia, Engelhardtiachrysolepis, Chloranthus glarber, Astilbe,microphylla, and so on. There has been reported that astilbin exhibitssome important bioactivities such as aldose reductase inhibitory effect,active oxygen extinguishing effect, carcinogenesis promotion inhibitoryeffect, anti-inflammatory effect, and so on (Japanese Patent PublicationNos. 97/30984, 94/65074, 94/247851, and 94/256194), and therefore,astilbin is to be a very useful compound as anti-allergic drug oranticancer drug.

Astilbin of the formula (I-c) is a specific compound having twoasymmetric carbon atoms at 2- and 3-positions of flavan skeleton, andrhamnose group is substituted at 3-position via O-glycosyl bound. Astereoisomer of astilbin, that is, neoastilbin, isoastilbin andneoisoastilbin, have same biological effects as those of astilbin, andfurther smitilbin or engeletin, analogous compound of astilbin, hasimproving effect for immune hepatic toxicity (Planta Med., 1999February, 65(1): 56-59).

It has been known that astilbin or analogues thereof, includingstereoisomeric compound, was obtained from plant matter (e.g., Astilbethunbergii Miq) by isolating and purification procedures. Further, themethod for isomerising of astilbin and stereoisomer thereof using basicaqueous solution has only been reported (Yakugaku Zasshi, 1959, 80:1202), and therefore, a chemical total synthesis of astilbin is notestablished up to now.

Hence the content of the objective compound in the plant matter isvaried depending on the picking season, picking place and so on, and isvery low, the isolating procedure from the plant matter is not availablefor industrial methods of producing said compound. Further, using thecompound isolated from the plant matter as a medicine has some troublesdue to the difficulties of separating from the analogous compounds andpurifying the compound.

Accordingly, the object of the present invention is to provide a processfor preparing a flavonoid compound having aldose reductase inhibitoryeffect, active oxygen extinguishing effect, carcinogenesis promotioninhibitory effect, anti-inflammatory effect, and so on. Moreparticularly, the object of the present invention is to provide theindustrial process for preparing astilbin and analogous thereof from theeasily obtainable starting compound with short process and convenientmeans in high yield and high purity of the compound.

DISCLOSURE OF INVENTION

In order to solve the problems, therefore, the present inventors havefound out that starting from readily available catechins, and reactingcatechins with saccharides to obtain O-glycoside compounds then,oxidizing the C(4) position of flavonoid skeleton of obtained compoundsto produce astilbin and analogous thereof in high yield by selectivelyprocess.

Accordingly, one aspect of the present invention is to provide a processfor preparing a compound represented by the following formula (I):

wherein, R² is a substituted or unsubstituted phenyl group; R⁷ is ahydrogen atom or a hydroxyl group; and n is an integer of 1 to 4,

which process is characterized in that reacting a compound of thefollowing formula (II):

wherein, R¹ is a hydroxyl protecting group; R² and n have the samemeanings mentioned above,

with a sugar compound of the following formula (III):

wherein, R³, R⁴ and R⁵ are independently each other, a hydrogen atom ora hydroxyl protecting group; R⁶ is a hydrogen atom, a hydroxyl group ora protected hydroxyl group; and X is a halogen atom or an acyloxy group,

to produce a compound of following formula (IV):

wherein, R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings mentionedabove,

then, conducting (a) or (b);

(a) oxidizing of 4-position of the flavonoid skeleton of the compound ofthe formula (IV) obtained above to produce a compound of the followingformula (V):

wherein, R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings mentionedabove,

or

(b) oxidizing of 4-position of the flavonoid skeleton of the compound ofthe formula (IV) to produce a compound of the following formula (VI):

wherein, R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings mentionedabove,

subsequently, further oxidizing of 4-position of the flavonoid skeletonof the compound of the formula (VI) obtained above to produce a compoundof the following formula (V):

wherein, R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings mentionedabove,

and finally, removing the hydroxyl protecting group of the compound (V),obtained by the above methods (a) or (b), to produce the compound of theformula (I).

Specific aspect of the present invention, it is provided a process forpreparing a compound represented by the following formula (I-a):

wherein, R² is a substituted or un-substituted phenyl group; R⁷ is ahydrogen atom or a hydroxyl group.

More specific aspect of the present invention is to provide a processfor preparing a compound represented by the following formula (I-b):

in which, the positions of hydroxyl groups at the flavonoid skeleton,and sugar derivative at 3-position are specified as mentioned aboveformula.

Still more specific aspect of the present invention is to provide aprocess for preparing a compound represented by the following formula(I-c):

that is, astilbin itself.

For the synthetic method of the compound of the formula (I) or thecompound of the formula (V), the direct reaction of flavonoid compoundhaving hydroxyl group at the 3-position and oxo group at the 4-positionwith the corresponding sugar derivative is thought as one method.However, the objective compound can't obtain by this method due to theinteraction of hydroxyl group at the 3-position and oxo group at the4-position of flavonoid skeleton.

According to the process of the present invention, the compound of theformula (I) or the compound of the formula (V) can be prepared fromreadily available compound and by industrial short process with highyield, and therefore, the present invention is superior one.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present specification, the substitute for the substituted phenylgroup represented by “R²” in the compound of formula (II) may behydroxyl group; hydroxyl group protected by the protecting group of R³,R⁴, R⁵, or R⁶, described later; preferably straight or blanched alkylgroup having 1 to 6 carbon atoms such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like;preferably straight or blanched alkoxy group having 1 to 6 carbon atomssuch as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, andthe like; amino group; amino group protected by the protecting group ofR³, R⁴, R⁵, or R⁶, described later; amide group; substituted amidegroup; lower acyl group such as acetyl, propionyl, tert-butyroyl,benzoyl and the like. In addition, number of the substitute and positionof the substitute are not limited respectively.

In the formula (III), halogen atom represented by “X” is chlorine,bromine, iodine and fluorine; acyloxy group may be lower acyloxy groupsuch as acetyloxy, propionyloxy, tert-butyroyloxy and the like, andaromatic acyloxy group such as benzoyloxy, toluyloxy and the like.

The present invention of process for preparing astilbin and analogousthereof is described in more detail by explaining the each step in thefollowing.

The following are chemical reaction scheme of process for preparingastilbin and analogous thereof of the present invention.

Wherein, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and n have the same meaningsmentioned above, and number in ◯ denotes process number.

The process of the present invention is comprises the Process 1 which isthe process for preparing the compound of the formula (IV) by reactingcatechins having protected hydroxyl group represented by the formula(II) with sugar derivatives of the formula (III); the Process 2 which isthe process for preparing the compound of the formula (V) by oxidizingthe compound (IV) obtained in the process 1; and the Process 3 which isthe process for preparing the objective compound of the presentinvention represented by the formula (I) by removing the hydroxylprotecting group of the compound (V) obtained in the Process 2.

In the Process 2, which is the process for preparing the compound of theformula (V) by oxidation of the 4-position of flavonoid skeleton of thecompound (IV), the reaction may be carried out by the following twomethods (a) or (b).

(a) Method for obtaining the compound (V) by direct oxidation of thecompound (IV) (Process {circle around (2)}-1), or

(b) Method for obtaining the compound (V) by converting the compound(IV) to the intermediate compound of the formula (VI) by introducinghydroxyl group at 4-position of flavonoid skeleton of the compound (IV)(Process {circle around (2)}-2a), then oxidation of the hydroxyl groupat the 4-position of the compound (VI) (Process {circle around (2)}-2b).

Each process is described in more detail in the following.

The Process 1 is the process for preparing the compound of the formula(IV) by reacting catechins having protected hydroxyl group of theformula (II) with sugar derivatives of the formula (III).

In catechins of the formula (II), substitute represented by “R²” issubstituted phenyl group. In case of the substitute of phenyl group ishydroxyl or amino group, these groups may be preferably protected by theprotective groups, which is non-limiting and easily removed off bycatalytic reduction, hydrolysis and enzyme reaction and the like (forexample, “Protective Groups In Organic Synthesis” 2nd. ed., T. W. Greenand P. G. M. Wuts, John Wiley & Sons, Inc., New York 1991). Examples ofthe protective group may include hydroxyl protecting group or aminoprotecting group such as benzyl, acetyl and the like commonly used inthe field of organic chemistry, and benzyl group is preferably used. Thecompound of the formula (II) is commercial available or may be preparedfrom a commercial available compound by the common method in thistechnical field.

Furthermore, in catechins of the formula (II), the substituterepresented by “R¹” may preferably be the hydroxyl protecting group, andthe hydroxyl group of the sugar derivative represented by the formula(III) may preferably be protected by R³, R⁴ and R⁵. The hydroxylprotecting group represented by R¹, R³, R⁴ and R⁵ is non-limiting andeasily removed by catalytic reduction, hydrolysis or enzyme reaction(for example, “Protective Groups In Organic Synthesis” 2nd. ed., T. W.Green and P. G. M. Wuts, John Wiley & Sons, Inc., New York 1991).Examples of the protective group include hydroxyl protecting group suchas benzyl, acetyl and the like commonly used in the field of organicchemistry, and benzyl group is preferably used. The group R⁶ of sugarderivative of the formula (III) may be hydrogen atom, hydroxyl group orhydroxyl group protected by R¹, R³, R⁴ and R⁵ mentioned above. Thecompound of the formula (III) is commercial available or may be preparedfrom a commercial available compound by the common method in thistechnical field.

The process can be carried out in the suitable solvent by reacting 1.0equivalent of the compound of the formula (II) with 0.5 to 2.0,preferably 1.0 equivalent of the compound of the formula (III) in thepresence of Cp₂HfCl₂ or Cp₂ZrCl₂ together with AgX (in which, Cp iscyclopentadienyl group; X is ClO₄ or CF₃SO₃), or in the presence ofLewis acid.

The amount of Cp₂HfCl₂ or Cp₂ZrCl₂ as the reaction regent may be 0.5 to2.0, preferably 1.0 to 1.5 equivalents based on 1.0 equivalent of thecompound of the formula (III). Further, 2.0 equivalents of AgX (inwhich, X is ClO₄ or CF₃SO₃) based on the amount of the reaction reagentmay be preferably used. Examples of AgX may include AgClO₄ or CF₃SO₃Ag.

In this reaction, Lewis acid may be used as the reaction reagent, andexamples of the Lewis acid may include trimethysilyl triflate[TMS(OTf)], di-t-butylsilyl ditriflate [t-Bu₂Si(OTf)₂], borontrifluoride etherate [BF₃OEt₂], t-butyldimethylsilyl ditriflate[t-BuMe₂Si(OTf)₂], tin chloride and the like. The amount of the Lewisacid may be 0.5 to 3.0, preferably 0.5 to 2.0 equivalents based on theamount of the compound (II).

The solvent to be used in the reaction may be non-limiting inertsolvent, for example halogenated hydrocarbons such as methylenechloride, ethylene chloride and the like; ethers such as diethyl ether,dioxane and the like; aromatic hydrocarbons such as toluene, benzene andthe like. In the light of reaction selectivity, reaction yield, handlingand so on, halogenated hydrocarbons such as methylene chloride oraromatic hydrocarbons such as toluene and benzene are preferably used.

The reaction time and reaction temperature are not strictly limited;however, the reaction temperature may range from −78° C. to 100° C.,particularly from −78° C. to the room temperature. The reaction time maybe decided by the index of the productivity of the purposed compound,and the compound of the formula (III) may be isolated and purified bysubjecting the reaction mixture to ordinary means in the field of theorganic chemistry such as condensation, extraction, solvent conversion,chromatography, and the like.

In this Process 1, the stereoisomer compound (optical isomer) due to theasymmetric carbon atoms of 2- and 3-positions of flavonoid skeleton canbe used for catechins of the formula (II), and in this case, thecompound (IV) having same configuration as the compound (II) can beobtained by the reaction with the compound of the formula (III).

Subsequently, the compound of the formula (IV) obtained by the Process 1can be converted to the compound of the formula (V) by oxidationreaction using an oxidizing reagent in the suitable solvent, by theProcess 2.

The oxidation reaction can be carried out by the following two methods(a) or (b).

(a) Method for obtaining the compound (V) by direct oxidation of thecompound (IV), or

(b) Method for obtaining the compound (V) by converting the compound(IV) to the intermediate compound of the formula (VI) by introducinghydroxyl group at 4-position of flavonoid skeleton, then, oxidation ofthe hydroxyl group at the 4-position of the compound (VI).

The oxidizing reagent used for the direct oxidation of the compound ofthe formula (IV) to obtain the compound of the formula (V) may be anytype of the oxidizing reagent, which is used for oxidation of the4-position of the flavonoid skeleton convert to oxo group, and leadtetraacetate, 2,3-dichloro-5,6-dicyanobenzoquinone (herein-afterreferred to as DDQ) or pyridinium dichromate (hereinafter referred to asPDC) is preferably used.

The solvent to be used in the oxidation reaction is not strictly limitedand may be inert solvent, for example halogenated hydrocarbons such asmethylene chloride, ethylene chloride and the like; ethers such asdioxane, tetrahydrofuran and the like; aromatic hydrocarbons such asbenzene, toluene, and the like; water, or the mixture solvent thereof.The reaction temperature may range from −78° C. to 100° C., preferablyat the room temperature. The reaction time may be decided by the indexof the productivity of the purpose compound, and the purpose compound ofthe formula (V) can be obtained in the good yield.

On the other hand, the oxidizing reagent used for the oxidation of thecompound of the formula (IV) to obtain the intermediate compound of theformula (VI) by introducing hydroxyl group at 4-position of flavonoidskeleton, and then, oxidation of the hydroxyl group at the 4-position ofthe compound (VI) to obtain the compound of the formula (V) may be forexample lead tetraacetate, 2,3-dichloro-5,6-dicyanobenzoquinone and thelike. By using DDQ as the oxidizing reagent, hydroxyl group can beintroduced at 4-position of flavonoid skeleton in good yield.

The oxidation reaction can be carried out in the suitable solvent, andexamples of the solvent may include halogenated hydrocarbons such asmethylene chloride, ethylene chloride and the like; ethers such asdioxane, tetrahydrofuran and the like; water, or the mixture solventthereof, the mixture solvent of methylene chloride and water ispreferably used. The reaction temperature may range from −78° C. to 100°C., preferably at the room temperature. The reaction time may be decidedby the index of the productivity of the purposed compound.

Then, the compound of the formula (VI) having hydroxyl group at4-position of flavonoid skeleton is derived into the compound of theformula (V) by oxidation reaction of hydroxyl group to oxo group. Theoxidizing reagent used for this reaction may be any type of theoxidizing reagent, which is used for oxidation of hydroxyl group, andpyridinium dichromate is preferably used.

The oxidation reaction of hydroxyl group can be carried out in thesuitable solvent, and examples of the solvent may include halogenatedhydrocarbons such as methylene chloride, ethylene chloride and the like;aromatic hydrocarbon such as benzene, toluene and the like; water, orthe mixture solvent thereof. By using methylene chloride as the reactionsolvent, the oxidation reaction can lead to a good result. The reactiontemperature is not strictly limited and may range from −78° C. to 100°C., preferably at the room temperature. The reaction time may be decidedby the index of the productivity of the purposed compound.

Then, by the Process 3, the compound of the formula (V) obtained in theProcess 2 is converted to astilbin and analogous thereof represented bythe formula (I), which is the objective compound of the presentinvention, by removing the hydroxyl protecting group (de-protectivereaction) of the compound (V).

The condition of the removing reaction of the hydroxyl protecting groupin the Process 3 may vary depending on the variety of the hydroxylprotecting group. For example, in case of benzyl group is used as theprotective group, the benzyl group can preferably removed by thehydrogenation reaction using of the catalyst. Examples of the catalystmay include Raney nickel, palladium-carbon (5 to 20%), palladium-black,platinum and the like, and the reaction can be carried out underhydrogen gas atmospheric pressure with stirring.

The reaction described above provides astilbin and analogues thereofrepresented by the formula (I) of the present invention, and thecompound of the formula (I) may be obtained in purity form after thereaction by the ordinary means in the field of the organic chemistrysuch as condensation, extraction, solvent conversion, chromatography,and the like.

EXAMPLE

The present invention is described in more detail in the following byway of working examples; however, it is to be understood that thepresent invention is not limited to the examples.

In the description of the example, number in parenthesis is the numberof the compound, and the symbols listed below are used to have theparticular meanings respectively.

Ac acetyl group Bn benzyl group OTf CF₃SO₃ Cp cyclopentadienyl group

Example 1

To a mixture solution of 83.0 mg (0.218 mmol) of Cp₂HfCl₂ and 90.8 mg(0.439 mmol) of AgClO₄ in methylene chloride in the presence of 214 mgof pulverized and dried desiccant (molecular sieve 4A) were sequentialadded a solution of 127 mg (0.195 mmol) of Compound (1) in methylenechloride (3.0 ml) and a solution of 93.7 mg (0.197 mmol) of Compound (2)in methylene chloride (3.0 ml) at −78° C. Then, the temperature of thereaction mixture was gradually increased up to −35° C. during 1 hour,and the reaction mixture was stirred for 1 hour at the same temperature.After the reaction, saturated sodium hydrogen carbonate aqueous solution(2.0 ml) was added dropwise to the reaction mixture, and insolublematerials were removed off by Celite® filtration. Water was added to theobtained filtrate, and the mixture was extracted with ethyl acetate(thrice). The combined organic layer was washed with brine and driedover with anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the resultant crude product was purified bypreparative silica gel chromatography (benzene/ethyl acetate=98/2) toobtain 70.1 mg (yield: 82%) of Compound (3) as white solid.

Data of the instrumental analysis of the Compound (3) were as follow:

Melting point: 36-38° C.

[α]_(D) ²²: +26.2 (c=1.05, CHCl₃)

¹H-NMR (500 MHz, CDCl₃) δ 1.27 (d, 3H, J=6.3 Hz), 2.66 (dd, 1H, J=16.5,9.0 Hz), 3.06 (dd, 1H, J=16.5, 6.0 Hz), 3.36 (dd, 1H, J₁=3.0, J₂=1.5Hz), 3.52 (dd, 1H, J₁=9.5, J₂=9.5 Hz), 3.75 (dd, 1H, J₁=9.5, J₂=3.0 Hz),3.79 (dq, 1H, J₁=9.5, J₂=6.3 Hz), 3.96 (ddd, 1H, J₁=9.0, J₂=9.0, J₃=6.0Hz), 4.20 (d, 1H, J=12.5 Hz), 4.259 (d, 1H, J=1.5 Hz), 4.263 (d, 1H,J=12.5 Hz), 4.48 (d, 1H, J=11.5 Hz), 4.54 (d, 1H, J=11.5 Hz), 4.59 (d,1H, J=10.8 Hz), 4.60 (d, 1H, J=9.0 Hz), 4.89 (d, 1H, J=10.8 Hz), 4.98(s, 2H), 5.03 (d, 1H, J=12.0 Hz), 5.05 (d, 1H, J=12.0 Hz), 5.09 (s, 2H),5.12 (s, 2H), 6.18 (d, 1H, J=2.5 Hz), 6.24 (d, 1H, J=2.5 Hz), 6.90 (dd,1H, J₁=8.0, J₂=1.5 Hz), 6.90 (dd, 1H, J=8.0 Hz), 7.06 (d, 1H, J=1.5 Hz),7.19-7.21 (m, 5H), 7.25-7.43 (m, 30H).

¹³C-NMR (125 MHz, CDCl₃) δ 17.9, 27.9, 68.5, 70.0, 70.1, 71.3, 71.4,71.9, 72.4, 74.2, 75.4, 75.5, 79.7, 80.1, 80.4, 93.9, 94.4, 98.1, 102.5,114.0, 114.7, 120.8, 127.12, 127.14, 127.39, 127.41, 127.50, 127.54,127.7, 127.80, 127.84, 127.9, 128.0, 128.1, 128.2, 128.3, 128.4,128.475, 128.483, 128.5, 128.6, 131.9, 136.9, 136.96, 137.00, 137.1,138.2, 138.5, 138.7, 149.1, 149.2, 155.3, 157.6, 158.8.

IR (KBr): cm⁻¹ 3030, 2910, 2865, 1950, 1875, 1810, 1750, 1620, 1590,1515, 1500, 1455, 1430, 1375, 1310, 1260, 1215, 1145, 1120, 1095, 910,840, 810, 735, 695, 615.

Elemental analysis for C₇₀H₆₆O₁₀ Calcd.: C, 78.78; H, 6.23. Found: C,77.82; H, 6.23.

Example 2

A mixture solution of 87.4 mg (0.134 mmol) of Compound (1) and 64.3 mg(0.135 mmol) of Compound (2) in methylene chloride (4.0 ml) in thepresence of 204 mg of pulverized and dried desiccant (molecular sieve4A) was cooled to −78° C. To this mixture was added a solution oft-Bu₂Si(OTf)₂ in methylne chloride (0.48 ml: 0.15 mmol), then, thetemperature of the reaction mixture was gradually increased up to −20°C. during 3 hours, and the reaction mixture was stirred for 50 minutesat the same temperature. After the reaction, aqueous saturated sodiumhydrogen carbonate solution (2.0 ml) was added dropwise to the reactionmixture, and insoluble materials were removed off by Celite® filtration.Water was added to the obtained filtrate, and the mixture was extractedwith ethyl acetate (thrice). The combined organic layer was washed withbrine and dried over anhydrous sodium sulfate. The solvent was removedoff under reduced pressure, and the resultant crude product was purifiedby preparative silica gel chromatography (benzene/ethyl acetate=97/3) toobtain 109 mg (yield: 76%) of Compound (3) as colorless solid and 12.5mg (yield: 9%) of stereoisomer of Compound (3) as colorless solid, as byproduct.

Data of the instrumental analysis of the Compound (3) were identifiedwith those obtained in Example 1.

Example 3

The Compound (3) was obtained by repeating the same reaction describedin the Example 2, by replacing the reaction solvent and the reactionreagent as indicated in the following table.

The yields were summarized in the following table.

Yield (%) Reaction Reaction Reaction of the Reagent Temperature SolventCompound (3) Cp₂ZrCl₂—AgClO₄ −78° C.˜−35° C. CH₂Cl₂ 74 Cp₂ZrCl₂—Ag(OTf)−78° C.˜room tempt. CH₂Cl₂ 3 BF₃OEt₂ −78° C.˜room tempt. CH₂Cl₂ 38 SnCl₄−78° C.˜−28° C. CH₂Cl₂ 10 TMS(OTf) −78° C.˜−30° C. CH₂Cl₂ 55Ph₂SiCl₂—AgClO₄ −78° C.˜−40° C. CH₂Cl₂ 43 t-Bu₂Si(OTf)₂ −78° C.˜roomtempt. CH₂Cl₂ 66 i-Pr₃Si(OTf) −78° C.˜room tempt. CH₂Cl₂ 63t-Bu₂Si(OTf)₂ −78° C.˜−10° C. CH₂Cl₂ 52 t-Bu₂Si(OTf)₂ −78° C.˜roomtempt. Ether 61 t-Bu₂Si(OTf)₂ −78° C.˜room tempt. Benzene 70t-Bu₂Si(OTf)₂ 0° C. Toluene 68

Example 4

To a solution of 28.5 mg (0.0267 mmol) of Compound (3) in methylenechloride (2.7 ml) were sequential added 12.6 mg (0.0555 mmol) of2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and water (0.14 ml; 7.8mmol), and the mixture was stirred for 5 hours at the room temperature.The reaction mixture was cooled to 0° C., then water and ether wereadded to the mixture. The mixture was extracted with ether (thrice) andthe combined organic layer was washed with saturated aqueous sodiumhydrogen carbonate solution (twice) and brine (thrice), and dried overwith anhydrous sodium sulfate. The solvent was removed off under reducedpressure, and the resultant crude product was purified by preparativesilica gel chromatography (benzene/ethyl acetate=95/5) to obtain 19.1 mg(yield: 66%) of Compound (4) as colorless solid.

Data of the instrumental analysis of the Compound (4) were as follow:

Melting point: 40-42° C.

[α]_(D) ²³: +36.7 (C=1.04, CHCl₃)

¹H-NMR (500 MHz, CDCl₃) δ 1.28 (d, 3H, J=6.0 Hz), 2.46 (brs, 1H,OH),3.36 (dd, 1H, J₁=3.0, J₂=1.5 Hz), 3.51 (dd, 1H, J₁=J₂=9.5 Hz), 3.73(dd, 1H, J₁=9.5, J₂=3.0 Hz), 3.83 (dq, 1H, J₁=9.5, J₂=6.0 Hz), 3.95 (dd,1H, J₁=10.0, J₂=3.0 Hz), 4.09 (d, 1H, J=12.5 Hz), 4.18 (d, 1H, J=12.5Hz), 4.20 (d, 1H, J=1.5 Hz), 4.45 (d, 1H, J=12.0 Hz), 4.53 (d, 1H,J=12.0 Hz), 4.58 (d, 1H, J=11.0 Hz), 4.88 (d, 1H, J=11.0 Hz), 4.97 (d,1H, J=13.0 Hz), 4.99 (d, 1H, J=13.0 Hz), 5.06-5.11 (m, 5H), 5.12-5.15(m, 3H), 6.15 (d, 1H, J=2.0 Hz), 6.25 (d, 1H, J=2.0 Hz), 6.95 (d, 1H,J=8.0 Hz), 7.01 (dd, 1H, J₁=8.0, J₂=2.0 Hz), 7.14 (d, 1H, J=2.0 Hz),7.16-7.42 (m, 35H).

¹³C-NMR (125 MHz, CDCl₃) δ 17.9, 61.9, 69.0, 70.1, 70.3, 71.2, 71.4,72.0, 72.4, 74.7, 75.31, 75.34, 77.1, 79.5, 80.1, 94.3, 94.4, 98.5,104.7, 114.5, 114.6, 121.1, 127.1, 127.37, 127.41, 127.45, 127.48,127.5, 127.6, 127.7, 127.8, 127.88, 127.93, 128.0, 128.1, 128.2, 128.3,128.4, 128.47, 128.49, 128.59, 128.61, 131.3, 136.6, 136.7, 136.9,137.0, 138.0, 138.4, 138.5, 149.1, 149.4, 155.9, 158.6, 160.9.

IR (KBr): cm⁻¹ 3435, 3030, 2915, 1615, 1595, 1515, 1495, 1455, 1430,1375, 1265, 1210, 1150, 1120, 1050, 1030, 905, 810, 735, 695, 624.

Example 5

To a solution of 35.7 mg (0.0330 mmol) of Compound (4) in methylenechloride (3.0 ml) was added pyridinium dichromate (24.9 mg; 0.0662 mmol)at 0° C., and the mixture was stirred for 21 hours at the roomtemperature. Then, pyridinium dichromate (26.9 mg; 0.0715 mmol) wasfurther added to the reaction mixture at 0° C., and the mixture wasstirred for 19 hours at the room temperature. After the reaction mixturewas cooled to 0° C., the reaction was stopped by adding ether. Themixture was filtrated by Celite® and the solvent was removed off underreduced pressure. The resultant crude product was purified bypreparative silica gel chromatography (benzene/ethyl acetate=95/5) toobtain 30.2 mg (yield: 85%) of Compound (5) as colorless solid.

Data of the instrumental analysis of the Compound (5) were as follow:

Melting point: 47-49° C.

[α]_(D) ²⁴: +25.7 (C=1.03, CHCl₃)

¹H-NMR (500 MHz, CDCl₃) δ 1.22 (d, 3H, J=6.0 Hz), 3.47 (dd, 1H, J₁=3.3,J₂=1.5 Hz), 3.52 (dd, 1H, J₁=J₂=9.5 Hz), 3.91 (dd, 1H, J₁=9.5, J₂=3.3Hz), 4.179 (d, 1H, J=1.5 Hz), 4.180 (d, 1H, J=12.5 Hz), 4.23 (d, 1H,J=12.5 Hz), 4.33 (dq, 1H, J₁=9.5, J₂=6.0 Hz), 4.44 (d, 1H, J=11.0 Hz),4.49 (d, 1H, J=11.5 Hz), 4.61 (d, 2H, J=11.5 Hz), 4.90 (d, 1H, J=11.5Hz), 5.01 (s, 2H), 5.08 (s, 2H), 5.12 (d, 1H, J=11.0 Hz), 5.13 (s, 2H),5.19 (s, 2H1), 6.16 (d, 1H, J=2.2 Hz), 6.21 (d, 1H, J=2.2 Hz), 6.94 (d,1H, J=8.0 Hz), 6.98 (dd, 1H, J₁=8.0, J₂=2.0 Hz), 7.12 (d, 1H, J=2.0 Hz),7.18-7.43 (m, 33H), 7.52 (d, 2H, J=7.5 Hz).

¹³C-NMR (125 MHz, CDCl₃) δ 17.9, 68.8, 70.3, 70.5, 71.2, 71.4, 72.2,72.4, 74.9, 76.0, 78.2, 79.7, 80.4, 82.3, 94.7, 95.6, 98.0, 105.5,114.0, 114.5, 126.5, 127.1, 127.3, 127.29, 127.33, 127.38, 127.39,127.50, 127.52, 127.6, 127.8, 127.86, 127.93, 128.1, 128.2, 128.4,128.50, 128.52, 128.6, 128.7, 129.6, 135.7, 136.4, 136.8, 136.9, 138.3,138.9, 139.0, 149.2, 149.8, 161.2, 163.9, 164.8, 186.7.

IR (KBr): cm⁻¹ 3030, 2930, 1955, 1695, 1610, 1575, 1515, 1455, 1430,1380, 1265, 1235, 1215, 1165, 1115, 1030, 820, 750, 695, 670.

Elemental analysis for C₇₀H₆₄O₁₁ Calcd.: C, 77.76; H, 5.97. Found: C,77.54; H, 6.27.

Example 6

To a solution of 39.5 mg (0.0365 mmol) of Compound (5) in methanol (5.0ml) was added palladium black (3.0 mg), and the mixture was stirred for20 hours under hydrogen atmosphere at the room temperature. Then,palladium black (3.0 mg) was further added to the reaction mixture andthe mixture was stirred for 30 hours under hydrogen atmosphere. Afterthe reaction mixture was leaved for rest, the supernatant liquid wascollected, and the residue stirred with methanol. After the mixture wasleaved for rest, the supernatant liquid was collected. This procedurewas repeated thrice. All collected was combined and removed off underreduced pressure. The resultant residue was purified by Sephadex® LH-20to obtain 14.9 mg (yield: 91%) of Compound (6) [astilbin] as colorlesssolid.

Data of the instrumental analysis of the Compound (6) were as follow:

¹H-NMR (500 MHz, CDCl₃) δ 1.18 (d, 3H, J=6.0 Hz), 3.30 (dd, 1H,J₁=J₂=9.5 Hz, overlapping with MeOH), 3.54 (dd, 1H, J₁=3.3, J₂=1.3Hz),3.65 (dd, 1H, J₁=9.5, J₂=3.3 Hz),4.05(d, 1H, J=1.3 Hz), 4.23 (dq,1H, J₁=9.5, J₂=6.0 Hz), 4.56 (d, 1H, J=10.5 Hz), 5.06 (d, 1H, J=10.5Hz), 5.89(d, 1H, J=2.0 Hz), 5.91 (d, 1H, J=2.0 Hz), 6.80 (d, 1H, J=8.3Hz), 6.83 (dd, 1H, J₁=8.3, J₂=1.8 Hz), 6.95 (d, 1H, J=1.8 Hz).

¹³C-NMR (125 MHz, CD₃OD) δ 18.6, 71.3, 72.6, 73.0, 74.6, 79.4, 84.7,97.1, 98.2.

INDUSTRIAL APPLICABILITY

As described above, the present invention is to provide a process forpreparing a flavonoid compound having aldose reductase inhibitoryeffect, active oxygen extinguishing effect, carcinogenesis promotioninhibitory effect, anti-inflammatory effect, and so on, moreparticularly, to provide the industrial process for preparing astilbinand analogous thereof from the easily obtainable starting compound withshort process and convenient means in high yield and high purity of thecompound, and therefore, the present invention makes a greatcontribution to the medical and pharmaceutical industry.

What is claimed is:
 1. A process for preparing a compound represented bythe following formula (I):

wherein, R² is a substituted or un-substituted phenyl group; R⁷ is ahydrogen atom or a hydroxyl group; and n is an integer of 1 to 4; whichprocess is characterized in that reacting a compound of the followingformula (II):

wherein, R¹ is a hydroxyl protecting group; R² and n have the samemeanings mentioned above, with a sugar compound of the following formula(III):

wherein, R³, R⁴ and R⁵ are independently each other, a hydrogen atom ora hydroxyl protecting group; R⁶ is a hydrogen atom, a hydroxyl group ora protected hydroxyl group; and X is a halogen atom or an acyloxy group,to produce a compound of following formula (IV):

wherein, R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings mentionedabove, then, oxidizing of 4-position of the flavonoid skeleton of thecompound of the formula (IV) obtained above to produce a compound of thefollowing

wherein, R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings mentionedabove, and removing the hydroxyl protecting group of the compound of theformula (V) obtained above to produce the compound of the formula (I).2. A process for preparing a compound represented by the followingformula (I):

wherein, R² is a substituted or un-substituted phenyl group; R⁷ is ahydrogen atom or a hydroxyl group; and n is an integer of 1 to 4; whichprocess is characterized in that reacting a compound of the followingformula (II):

wherein, R¹ is a hydroxyl protecting group; R² and n have the samemeanings mentioned above, with a sugar compound of the following formula(III):

wherein, R³, R⁴ and R⁵ are independently each other, a hydrogen atom ora hydroxyl protecting group; R⁶ is a hydrogen atom, a hydroxyl group ora protected hydroxyl group; and X is a halogen atom or an acyloxy group,to produce a compound of following formula (IV):

wherein, R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings mentionedabove, then, oxidizing of 4-position of the flavonoid skeleton of thecompound of the formula (IV) obtained above to produce a compound of thefollowing formula (VI):

wherein, R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings mentionedabove, subsequently, further oxidizing of 4-position of the flavonoidskeleton of the compound of the formula (VI) obtained above to produce acompound of the following formula (V):

wherein, R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings mentionedabove, and removing the hydroxyl protecting group of the compound of theformula (V) obtained above to produce the compound of the formula (I).3. A process for preparing a compound represented by the followingformula (I):

wherein, R² is a substituted or un-substituted phenyl group; R⁷ is ahydrogen atom or a hydroxyl group; and n is an integer of 1 to 4; whichprocess is characterized in that oxidizing of 4-position of theflavonoid skeleton of a compound of the following formula (IV):

wherein, R¹ is a hydroxyl protecting group; R² is a substituted orun-substituted phenyl group; R³, R⁴ and R⁵ are independently each other,a hydrogen atom or a hydroxyl protecting group; R⁶ is a hydrogen atom, ahydroxyl group or a protected hydroxyl group; and n is an integer of 1to 4, to produce a compound of the following formula (V):

wherein, R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings mentionedabove, and removing the hydroxyl protecting group of the compound of theformula (V) obtained above to produce the compound of the formula (I).4. A process for preparing a compound represented by the followingformula (I):

wherein, R² is a substituted or un-substituted phenyl group; R⁷ is ahydrogen atom or a hydroxyl group; and n is an integer of 1 to 4; whichprocess is characterized in that oxidizing of 4-position of theflavonoid skeleton of a compound of the following formula (IV):

wherein, R¹ is a hydroxyl protecting group; R² is a substituted orun-substituted phenyl group; R³, R⁴ and R⁵ are independently each other,a hydrogen atom, a hydroxyl group or a hydroxyl protecting group; R⁶ isa hydrogen atom, a hydroxyl group or a protected hydroxyl group; and nis an integer of 1 to 4; to produce a compound of the following formula(VI):

wherein, R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings mentionedabove, subsequently, further oxidizing of 4-position of the flavonoidskeleton of the compound of the formula (VI) obtained above to produce acompound of the following formula (V):

wherein, R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings mentionedabove, and removing the hydroxyl protecting group of the compound of theformula (V) obtained above to produce the compound of the formula (I).5. The process according to any one of claims 1 to 4, wherein thecompound of the formula (I) is a compound of the following formula(I-a):

wherein, R² is a substituted or un-substituted phenyl group; R⁷ is ahydrogen atom or a hydroxyl group.
 6. The process according to any oneof claims 1 to 4, wherein the compound of the formula (I) is a compoundof the following formula (I-b):


7. The process according to any one of claims 1 to 4, wherein thecompound of the formula (I) is a compound of the following formula(I-c):


8. A process for preparing a compound represented by the followingformula (V):

wherein, R¹ is a hydroxyl protecting group; R² is a substituted orun-substituted phenyl group; R³, R⁴ and R⁵ are independently each other,a hydrogen atom or a hydroxyl protecting group; R⁶ is a hydrogen atom, ahydroxyl group or a protected hydroxyl group; and n is an integer of 1to 4, which process is characterized in that oxidizing of 4-position ofthe flavonoid skeleton of a compound of the following formula (IV):

wherein, R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings mentionedabove.
 9. A process for preparing a compound represented by thefollowing formula (V):

wherein, R¹ is a hydroxyl protecting group; R² is a substituted orun-substituted phenyl group; R³, R⁴ and R⁵ are independently each other,a hydrogen atom or a hydroxyl protecting group; R⁶ is a hydrogen atom, ahydroxyl group or a protected hydroxyl group; and n is an integer of 1to 4, which process is characterized in that oxidizing of 4-position ofthe flavonoid skeleton of a compound of the following formula (IV):

wherein, R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings mentionedabove, to produce a compound of the following formula (VI):

wherein, R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings mentionedabove, and further oxidizing of 4-position of the flavonoid skeleton ofthe compound of the formula (VI) obtained above to produce a compound ofthe following formula (V).